UHRF1 plays an oncogenic role in small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is a malignant tumor characterized by aggressiveness and dismal prognosis. The specific role of ubiquitin‐like PHD and RING finger domain (UHRF1), a frequently overexpressed cancer‐promoting gene in various tumors, is poorly understood in SCLC. Herein, we explored the potential carcinogenic role of UHRF1 in SCLC. First, public databases were used to analyze the expression of UHRF1 in SCLC, and tissue specimens in our center were examined to confirm the results while clinical outcomes were collected to analyze its relationship with UHRF1. Then, UHRF1 knockdown and overexpression cell lines were established to evaluate the carcinogenic function of UHRF1 in vitro and in vivo. The mechanism of the biological consequences was determined by co‐inmunoprecipitation. Moreover, we also analyzed the influence of UHRF1 on cisplatin (DDP) sensitivity of SCLC. The expression of UHRF1 was significantly higher in SCLC tissues than in normal tissues, and high levels of UHRF1 suggested a poor prognosis for SCLC. Mechanistically, UHRF1 promoted SCLC growth through yes‐associated protein 1 (YAP1). Specifically, UHRF1 bound to YAP1 and inhibited YAP1 ubiquitin degradation, thus stabilizing the YAP1 protein in SCLC cells. UHRF1 downregulation enhanced DDP sensitivity in SCLC cells and was correlated with a favorable prognosis in patients with SCLC treated with platinum‐based chemotherapy. UHRF1 plays an oncogenic role in SCLC by modulating YAP1. Therefore, UHRF1 could be used as a biomarker to predict the prognosis of SCLC patients and serve as a potential therapeutic target for SCLC patients.

Roles of post-translational modifications of UHRF1 in cancer

“…UHRF1 overexpression has been found in various sub-types of lung cancer, and can be used for the precision diagnose of lung cancer [ 78 ]. UHRF1 expression levels are significantly elevated in small cell lung cancer (SCLC) and are closely associated with poor prognosis [ 79 ]. Mechanistically, UHRF1 binds to YAP1 (the major downstream effector protein of the Hippo signaling pathway) and inhibits the ubiquitination-dependent protein degradation, thereby stabilizing YAP1 protein in tumor cells of SCLC (Fig.…”

Oncogenic Roles of UHRF1 in Cancer

“…UHRF1 has been identified as a significant promoter of cell proliferation and tumor growth in numerous cancers, including retinoblastoma, osteosarcoma, lung cancer, and breast cancer [ 14 , 18 , 20 , 62 , 65 ]. Specifically, in small cell lung cancer (SCLC), UHRF1 promotes SCLC proliferation through its interaction with the yes-associated protein 1 (YAP1), preventing YAP1 ubiquitination and degradation [ 62 ].…”

“…UHRF1 has been identified as a significant promoter of cell proliferation and tumor growth in numerous cancers, including retinoblastoma, osteosarcoma, lung cancer, and breast cancer [ 14 , 18 , 20 , 62 , 65 ]. Specifically, in small cell lung cancer (SCLC), UHRF1 promotes SCLC proliferation through its interaction with the yes-associated protein 1 (YAP1), preventing YAP1 ubiquitination and degradation [ 62 ]. In non-small cell lung cancer (NSCLC), the expression of long non-coding RNA UHRF1 Protein-Associated Transcript (UPAT) contributes to UHRF1 overexpression, which leads to an increase in cell proliferation and enhances the transition from the G1 to the S phase of the cell cycle [ 63 ].…”

“…One retinoblastoma study showed that the targeted depletion of UHRF1 significantly enhances the sensitivity of retinoblastoma cells to a panel of chemotherapeutic agents including etoposide, camptothecin, and carboplatin [ 66 ]. A study on SCLC, characterized by an aggressive course and a poor prognosis, showed that reducing UHRF1 levels increased the chemosensitivity of SCLC cells to cisplatin, a cornerstone in the combination chemotherapy regimen for this type of lung cancer [ 62 ]. Another study on KRAS mutant lung adenocarcinoma identified UHRF1 as a critical target for cardiac glycosides, potent DSB repair inhibitors, in sensitizing KRAS mutant lung cancer to chemotherapy [ 68 ].…”

YTHDF1 promotes gallbladder cancer progression via post‐transcriptional regulation of the m6A/UHRF1 axis

“…11,12 UHRF1 regulates various epigenetic markers, including repressive epigenetic markers, such as m5C methylation, as well as active chromatin mark, such as H3K4me3, leading to transcription factor-like activity. 13 Previous study revealed that depletion of UHRF1 promoted apoptosis, 14,15 cell cycle arrest, 14 metastases, 16 epithelial-mesenchymal transition, 17 and acted as an oncogene in multiple cancers, including small cell lung cancer, 18 pancreatic cancer, 19 intrahepatic cholangiocarcinoma 20 and GBC. 14 In this study, we suppose to investigate the clear functions of YTHDF1 and m6A-dependent functions on regulating m6A/UHRF1 axis in gallbladder cancer progression.…”